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Pearls & Oy-sters: "Not multiple sclerosis" and the changing face of HTLV-1

A case report of downbeat nystagmus

From the Departments of Neurology (L.R.B., E.M.F., T.C.F., G.M.R.) and Ophthalmology (E.M.F.), University of Texas Southwestern Medical Center at Dallas; and Department of Neurology (S.L., M.C.L.), MS Center and Lab of Viral and Demyelinating Diseases, University of Tennessee Health Science Center, Memphis.

Address correspondence and reprint requests to Dr. Lakshmi Beeravolu, Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235 doclakshmi{at}gmail.com. 1. Daroff RB, Dell'Osso LF. Correspondence re: "Not multiple sclerosis" and the changing face of HTLV-1: a case report of downbeat nystagmus. Frohman EM, Beeravolu LR, Frohman TC, Remington GM, Lee S, Levin MC. Reply from the authors. Neurology 2009;73;1812–1813.[Medline]

	PEARLS

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• In the absence of typical clinical and radiologic features suggestive of MS, all other mimics of demyelinating disease need to be thoroughly excluded.
  
• HTLV-1 infection has been reported to cause extraspinal neurologic manifestations and should be included in the evaluation of suspected demyelinating disease, both of brain and spinal cord.
  
• Since HTLV-1 is known mainly to cause spinal cord atrophy, no imaging abnormalities may be seen in early stages of infection. Atrophy and magnetic resonance signal changes may be seen during advanced stages of the disease.
  
• CSF HTLV-1 may be negative by ELISA in 20% of cases despite serum studies being positive. Consider repeat testing in such cases.
  

Human T-cell lymphotropic virus–1 (HTLV-1) is endemic in Southern Japan, the Caribbean, and parts of western Africa, the Middle East, South America, and Melanesia.¹ HTLV-1 has a proven association with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), adult T-cell leukemia, and uveitis.^1,7 Some reports indicate a possible association with dermatitis, polymyositis, arthritis, pneumonitis, and Sjögren syndrome. The most widely reported neurologic manifestation of this condition is slowly progressive myelopathy, which may clinically resemble primary progressive multiple sclerosis (MS).^1,7,8 Extraspinal manifestations have been mostly limited to case reports and include cerebellar tremor, cognitive impairment, leukoencephalopathy, and optic neuritis.² Cerebellar symptoms as a presenting feature of HTLV-1 are rare.³ On extensive literature search, we found a case report of a Japanese woman with HTLV-1 presenting with downbeat nystagmus and cerebellar vermian atrophy.⁴ Another report from Scandinavia discusses three patients with HTLV-1-associated spinocerebellar syndrome.³ Overall, there have been nearly 14 cases of HTLV-associated cerebellar involvement reported from Japan and Canada.

	CASE REPORT

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A 52-year-old African American woman with a history of benign paroxysmal positional vertigo and hypertension presented with worsening episodes of vertigo at rest. She had the onset of bowel and bladder incontinence 2 years preceding the onset of her vertigo. Her cognitive function was normal. Neurologic examination revealed primary position vertical pendular nystagmus with a strong downbeating vector. Her extraocular movements were intact. Tone and strength of her extremities was normal. Deep tendon reflexes were diffusely brisk with flexor plantars. She had intact sensation to all modalities. Gait was wide-based. No appendicular dysmetria was noted.

Electronystagmography showed primary position vertical pendular nystagmus with a fast downbeating vector, most consistent with a central origin (figure). Nystagmus dampened with downgaze and increased on upgaze (in opposition to Alexander’s law, according to which the amplitude of nystagmus increases with gaze in the direction of the fast phase). There was no effect of convergence on the nystagmus. Some adduction slowing was seen bilaterally from eccentric gaze to center target, suggesting the possibility of internuclear ophthalmoparesis, and implicating an occult lesion of the medial longitudinal fasciculus.

View larger version (77K): [in this window] [in a new window]   Figure Screen capture of nystagmus at primary position The upper two lines represent recordings from the horizontal channel and the lower two lines from the vertical channel.

Brain MRI showed a few discrete juxtacortical white matter lesions. There were no lesions perpendicular to the ventricle typical for MS. Brainstem images including T2 sequences were unremarkable. MRI of the spine was unremarkable.

CSF showed a remarkably elevated immunoglobulin G (IgG) index of 2.08 (normal range: 0.3 to 0.7), an IgG synthetic rate of 27.88 (normal range: <3), and oligoclonal bands. CSF angiotensin converting enzyme (ACE) and VDRL results were unremarkable. Serum erythrocyte sedimentation rate, antinuclear antibody, angiotensin-converting enzyme, dsDNA, antineutrophil cytoplasmic antibody, perinuclear neutrophil cytoplasmic antibody, and Lyme antibody were all unremarkable. Serum vitamin B12 and folate levels were normal. The patient was diagnosed with possible MS and treated with weekly beta-interferon 1a for 2 years, during which time she had recurrent attacks of uveitis, which were treated with short courses of topical and oral steroids. Chest CT showed no evidence of sarcoidosis.

Due to the unremarkable MRI findings and recurrent episodes of uveitis, we were not convinced the patient had MS. An evaluation was repeated and included testing for serum HTLV-1, which was positive by ELISA. This was confirmed by Western blot, which showed intense immunoreactivity with all antigens, including recombinant gp46-I (env) and gag antigens, thus confirming HTLV-1 infection.⁹ Western blot testing for HTLV-2 (ARUP Labs, Salt Lake City, UT) was negative. CSF HTLV-1 was negative initially but repeat testing 1 year later showed intense immunoreactivity by Western blot to all antigens in an identical pattern to that of serum. Of note, though, it has been reported that 20% of patients with spastic paraparesis who are positive for antibodies to HTLV-1 in serum are negative in CSF.¹⁰

	DISCUSSION

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This case illustrates the challenge in differentiating MS from HTLV-1-associated neurologic disease. Recurrent episodes of vertigo and nystagmus are not uncommon in patients with MS. However, the clinical pearls of this case that suggested a diagnosis different from MS were that the patient did not meet the MRI criteria for either relapsing remitting or primary progressive MS and that the patient had recurrent episodes of uveitis. The patient tested positive for HTLV-1 and in distinction to other cases associated with HTLV-1 infection, this patient lived in the United States and presented with a syndrome characterized by progressive episodes of vertigo and nystagmus, without tremor, dysmetria, or cerebellar atrophy by MRI.^2–5

Classically, patients infected with HTLV-1 develop HAM/TSP, a slowly progressive myelopathy characterized by spastic paraparesis, hyperreflexia, and early bladder symptoms.^5,6–9 Recent data suggest that clinicians should broaden their definition of HTLV-1-associated neurologic disease.^2,5,9 Specifically, several articles show that a significant proportion of patients develop extraspinal neurologic manifestations, including cerebellar syndromes, optic neuritis, intellectual impairment, and uveitis.^2–5 This has led several authors to suggest changing the name of HAM/TSP to either HTLV-1 neurologic complex or HTLV-1-associated myelo-neuro-encephalopathy.^2,5 Our case is congruent with these findings and emphasizes the importance of having a high index of suspicion to test for HTLV-1 in individuals with neurologic illness of unclear etiology.

Disclosure: Dr. Frohman has received speaking and consulting fees from Biogen and TEVA and speaking fees from Bayer. He has also received research grant support from Aspreva. Gina Remington has received consulting fees from Biogen and TEVA. Dr. Levin has received honoraria for educational activities from Biogen Idec and TEVA and is a consultant for Gerson Lehman group.

CORRECTION

"Not multiple sclerosis" and the changing face of HTLV-1: A case report of downbeat nystagmus

In the Resident & Fellow Section, Pearls and Oy-sters "‘Not multiple sclerosis’" and the changing face of HTLV-1: A case report of downbeat nystagmus" by L.R. Beeravolu et al. (Neurology® 2009;72:e119–e120), the figure was intended to display downbeating nystagmus, but because of an error in the polarity of the infrared oculogram, the fast phases of the nystagmus were beating upward. The figure legend should have read as follows:

The upper two lines represent recordings from the horizontal channel and the lower two lines from the vertical channel. Note that "up" actually indicates "downward eye movement."

In addition, the authors wish to point out that the numbers on the horizontal axis represent time in milliseconds, whereas those in the vertical axis are in units of pixels per degree. The authors apologize for the errors.1

This correction was published in the November 24, 2009, issue of Neurology (2009;73:1813).

	REFERENCES

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1. Proietti FA, Carneiro Proietti ABF, Bernadette CC, Murphy EL. Global epidemiology of HTLV-1 infection and associated diseases. Oncogene 2005;24:6058–6068.[Medline]
2. Njmanshi AK, Kuate CT, Muna WF. HTLV-1 and neurological disease: from TSP to HAM: What next? Neurologist 2007;13:391.[Medline]
3. Castillo LC, Gracia F, Roman GC, Levine P, Reeves WC, Kaplan J. Spinocerebellar syndrome in 3 cases of HTLV types 1 and 2: report of 3 cases from Panama. Acta Neurol Scand 2000;101:405–412.[Medline]
4. Waragai M, Takaya Y, Hayashi M. HAM with cerebellar atrophy presenting a down-beat nystagmus. Rinsho Shinkeigaku 1995;35:549–552.[Medline]
5. Araujo AQ, Silva MT. The HTLV-1 neurological complex. Lancet Neurol 2006;5:1068–1076.[Medline]
6. Hollsberg P, Haffler DA. Pathogenesis of diseases associated with HTLV-1 infection. N Engl J Med 1993;328:1173–1182.[Free Full Text]
7. Khan RB, Bertorini TE, Levin MC. HTLV-1 and its neurological complications. The Neurologist 2001;7:271–278.[Medline]
8. Lee SM, Morcos Y, Jang H, Stuart JM, Levin MC. HTLV-1 induced molecular mimicry in neurologic disease. Curr Top Microbiol Immunol 2005;296:125–136.[Medline]
9. Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis 2007;7:266–281.[Medline]
10. Spina-Franca A, Livramento JA, Machado LR, et al. HTLV-1 antibodies in serum and CSF in tropical spastic paraparesis in Brazil. Arq Neuropsiquiatr 1990;48:441–447.[Medline]

This Article Figures Only Full Text (PDF) Correspondence: Submit a response Correspondence: View responses Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Beeravolu, L. R. Articles by Levin, M. C. PubMed Articles by Beeravolu, L. R. Articles by Levin, M. C. Related Collections Viral infections Clinical neurology examination Nystagmus All Demyelinating disease (CNS) Multiple sclerosis